Crystalline dipeptides useful in the synthesis of elamipretide

ABSTRACT

Disclosed are crystalline forms of L-Lys(Boc)-Phe-NH 2  and Boc-D-Arg-DMT.

RELATED APPLICATIONS

This application is the U.S. National Stage of PCT/US19/24617, filedMar. 28, 2019; which claims the benefit of priority to U.S. ProvisionalPatent Application No. 62/651,430, filed Apr. 2, 2018.

BACKGROUND OF THE INVENTION

Elamipretide (MTP-131) is a mitochondria-targeting peptide compound withtherapeutic potential for treating diseases associated withmitochondrial dysfunction. Elamipretide contains four-amino acidresidues and has been synthesized according to typical linear andconvergent solution phase peptide synthesis methods. The syntheticroutes to generate elamipretide that have been used to date require thepreparation of various differentially protected peptides, such thatcertain protecting groups are selectively removed in order to subjectthe deprotected compound to peptide coupling, while other protectinggroups remain to prevent unwanted side reactions. Even with protectinggroups such coupling reactions and related steps generate impurities.Thus, there exists a need to develop new methods to purify elamipretidethat allow the purification after coupling reactions. Crystallization ofthe desired reaction products are one method of achieving the necessarypurification.

SUMMARY OF THE INVENTION

Disclosed are crystalline forms of L-Lys(Boc)-Phe-NH₂ and Boc-D-Arg-DMT,wherein DMT is an abbreviation for dimethyltyrosine, which areintermediates in the synthesis of elamipretide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the XRPD pattern of crystalline L-Lys(Boc)-Phe-NH₂. The peaklisting of the XRPD pattern depicted in FIG. 1 is described in Table 1.

FIG. 2 is the XRPD pattern crystalline Boc-D-Arg-DMT. The peak listingof the XRPD pattern depicted in FIG. 2 is described in Table 2.

DETAILED DESCRIPTION OF THE INVENTION

Elamipretide has been shown to have various therapeutic effects indiseases related to mitochondrial dysfunction. Previous synthetic routesto elamipretide presented challenges with respect to scale-up due toreliance on chromatographic separations to enrich levels of desiredintermediates. Herein are disclosed crystalline forms ofL-Lys(Boc)-Phe-NH₂ and Boc-D-Arg-DMT, which can be used as purifiedintermediates in the synthesis of elamipretide.

One aspect of the present invention relates to crystalline forms ofCompound (I):

-   -   which compound is also known as L-Lys(Boc)-Phe-NH₂.

A crystalline form of Compound (I) can be used in the synthesis ofelamipretide.

In certain embodiments, a polymorph of the crystalline form ischaracterized by powder X-ray diffraction (XRD). θ represents thediffraction angle, measured in degrees. In certain embodiments, thediffractometer used in XRD measures the diffraction angle as two timesthe diffraction angle θ. Thus, in certain embodiments, the diffractionpatterns described herein refer to X-ray intensity measured againstangle 2θ.

In certain embodiments, a crystalline form of Compound (I) is notsolvated (e.g., the crystal lattice does not comprise molecules of asolvent). In certain alternative embodiments, a crystalline form ofCompound (I) is solvated. In some cases, the solvent is water.

In one aspect, the invention features a crystalline form of Compound (I)which has characteristic peaks in the powder X-ray diffraction (XRPD)pattern as shown in FIG. 1.

In another aspect, the invention features a crystalline form of Compound(I) which has characteristic peaks in the powder X-ray diffraction(XRPD) pattern at values of two theta (° 2θ) as shown in Table 1.

In another aspect, the invention features a crystalline form of Compound(I) which has characteristic peaks in the powder X-ray diffraction(XRPD) pattern at values of two theta (° 2θ) of: 4.7, 6.2, 12.4, 15.8,16.5, 18.0, 18.2, 18.8, and 19.8.

In another aspect, the invention features a crystalline form of Compound(I) which has characteristic peaks in the powder X-ray diffraction(XRPD) pattern at values of two theta (° 2θ) of: 4.7, 6.2, 11.3, 12.4,13.3, 15.0, 15.8, 16.5, 17.0, 17.7, 18.0, 18.2, 18.8, 19.8, 22.0, and22.8.

The relative intensity, as well as the two theta value, of each peak inTable 1, as well as in FIG. 1, may change or shift under certainconditions, although the crystalline form is the same. One of ordinaryskill in the art should be able to determine readily whether a givencrystalline form is the same crystalline form as described in Table 1,as well as in FIG. 1, by comparing their XRPD data.

One aspect of the present invention relates to a crystalline form ofCompound (II):

-   -   which compound is also known as Boc-D-Arg-DMT, and may also be        drawn in the form of a zwitterion.

A crystalline form of Compound (II) can be used in the synthesis ofelamipretide.

In certain embodiments, a polymorph of the crystalline form ischaracterized by powder X-ray diffraction (XRD). θ represents thediffraction angle, measured in degrees. In certain embodiments, thediffractometer used in XRD measures the diffraction angle as two timesthe diffraction angle θ. Thus, in certain embodiments, the diffractionpatterns described herein refer to X-ray intensity measured againstangle 2θ.

In certain embodiments, a crystalline form of Compound (II) is notsolvated (e.g., the crystal lattice does not comprise molecules of asolvent). In certain alternative embodiments, a crystalline form ofCompound (II) is solvated. In some cases, the solvent is water.

In one aspect, the invention features a crystalline form of Compound(II) which has characteristic peaks in the powder X-ray diffraction(XRPD) pattern as shown in FIG. 2.

In another aspect, the invention features a crystalline form of Compound(II) which has characteristic peaks in the powder X-ray diffraction(XRPD) pattern at values of two theta (° 2θ) as shown in Table 2.

In another aspect, the invention features a crystalline form of Compound(II) which has characteristic peaks in the powder X-ray diffraction(XRPD) pattern at values of two theta (° 2θ) of: 9.3, 12.1, 16.6, 17.6,18.0, 18.8, and 19.4.

In another aspect, the invention features a crystalline form of Compound(II) which has characteristic peaks in the powder X-ray diffraction(XRPD) pattern at values of two theta (° 2θ) of: 9.3, 12.1, 13.7, 16.3,16.6, 17.6, 18.0, 18.8, 19.4, 21.3, 23.0, 24.2, and 25.1.

The relative intensity, as well as the two theta value, of each peak inTable 2, as well as in FIG. 2, may change or shift under certainconditions, although the crystalline form is the same. One of ordinaryskill in the art should be able to determine readily whether a givencrystalline form is the same crystalline form as described in Table 1,as well as in FIG. 1, by comparing their XRPD data.

EXAMPLES

Materials and Methods

Name RM0858 General Method (2607) Parent 2Theta Sample Name S-18-0011882SCC-169 File Name RM0858 General Method (2607) Scan Type CoupledTwoTheta/Theta Scan Mode Continuous PSD fast Start 2.000 End 40.016 StepSize 0.050 Time per Step 192.00 Anode Cu kα1 1.54 Generator kV 40.0Generator mA 40.0 PSD Opening 2.940 Detector Slit Opening Primary Sollerslit 2.500 Secondary Soller slit 2.500 Sample rotation speed 15.000Divergence Slit 0.600 Antiscatter Slit 3.000 Slit Mode Fixed

Example 1. L-Lys(Boc)-Phe-NH2 (Compound I)

Exemplary Synthetic Route

Synthesis of Compound 3

MW Molar Density BR Charge Name Amount (g) Volume (mL) (g/mol) EquivMoles g/mL Amt (kg) kg/kg Phe-NH2 HCl 950.00 950.00 200.67 1.00 4.734 —7.030 Cbz-Lys(Boc)-OH 1891.11 1891.11 380.44 1.05 4.971 — 13.990 1.99HOBt-H₂O 797.48 797.48 153.14 1.10 5.208 — 5.900 0.84 Dimethylacetamide3736.49 3987.71 87.12 — — 0.937 27.650 3.93 (DMAc) N-Methylmorpholine957.72 1041.00 101.15 2.00 9.468 0.920 7.080 1.01 (NMM) EDCI 952.91952.91 191.70 1.05 4.971 — 7.050 1.00 Anhydrous Ethyl 750.50 951.2046.07 — — 0.789 5.550 0.79 Alcohol (EtOH) Acetonitrile (ACN) 11202.7014252.80 84.93 — — 0.786 82.900 11.79 Acetonitrile (ACN) 11202.7014252.80 85.93 — — 0.786 82.900 11.79

Operation Charge Units Inert the reactor with nitrogen. 1 ChargeCompound 1 to reactor. 950.00 g 2 Charge Compound 2 to reactor. 1891.11g 3 Charge HOBt-H2O to reactor. 797.48 g 4 Charge DMAc to reactor.3736.49 g 5 Adjust solution to target 22° C. (19 to 25° C.) withagitation. 6 Agitate for 10-15 min at 22° C. (19 to 25° C.). 7 Slowlycharge NMM to reactor with moderate 957.72 g agitation. 8 Adjustsolution to target 7° C. (4 to 10° C.) with agitation. 9 Slowly chargeEDCI to reactor with vigorous 952.91 g agitation. 10 Adjust solution totarget 7° C. (4 to 10° C.) with vigorous agitation. 11 Charge EtOH toreactor with vigorous 750.50 g agitation. 12 Adjust solution to target22° C. (19 to 25° C.) with vigorous agitation. 13 Agitate vigorously for≥1 h at 22° C. (19 to 25° C.). IPC for Reaction Completion (≤1.0% Phe-0.169% a/a NH2 remaining) CRYSTALLIZATION 15 Charge ACN to the reactorwith vigorous 11202.70 g agitation. 16 Agitate vigorously for ≥5 h at22° C. (19 to 25° C.). 17 Verify crystallization successful. 18 Filterthe reaction to isolate the product (SCC-175). 19 Wash the product cakewith ACN and combine 11202.70 g with mother liquor. 20 Dry the productwith agitation and nitrogen bleed for at least 17 h.

Synthesis of Compound 1

Volume MW Molar Density BR Name Amt (mL) (g/mol) Equiv g/mL Charge Amtunits kg/kg Compound 3 2000.00 2000.00 526.63 1.00 15.700 kg 10% Pd/C200.00 200.00 106.42 10% w/w — 3.140 kg 0.20 (50% w/w wet) AnhydrousMethyl 14191.08 17918.03 32.04 — 0.792 111.400 kg 7.10 Alcohol (MeOH)Anhydrous Methyl 7000.00 8838.38 32.04 — 0.792 54.950 kg 3.50 Alcohol(MeOH) Water 7000.00 7000.00 18.02 1.000 54.950 kg 3.50 Water 8000.008000.00 18.02 1.000 62.800 kg 4.00 MeOH-Water (1:9) 8000.00 7896.000.987 62.800 kg 4.00 Solution Water (1:9 MeOH- 9000.00 9000.00 18.021.000 NA NA water make-up) Anhydrous Methyl 792.00 1000.00 33.04 — 0.792NA NA Alcohol (MeOH) (1:9 MeOH-water make-up)

Operation Charge Units REACTION (30 L Hydrogenator Main Reactor) Inertthe hydrogenation reactor with nitrogen. 1 Charge Pd/C (10%, 50% w/wwater, 20A597) to 200.00 g reactor. 2 Charge Compound 3 to reactor.2000.00 g 3 Charge MeOH to the reactor. 14191.08 g 4 Adjust solution totarget 22° C. (19 to 25° C.) with agitation. Inert the hydrogenationreactor with nitrogen. 5 Pressurize the reactor with hydrogen (20-25psi). 6 Agitate for ≥6 h at 22° C. (19 to 25° C.) and 20-25 psihydrogen. Note: Maintain the pressure at 20-25 psi hydrogen. 7De-pressurize the reactor and inert with nitrogen at 22° C. (19 to 25°C.). IPC for Reaction Completion (≤0.5% SCC-175 0.09% a/a remaining) 9Filter the reaction to remove catalyst. 10 Rinse the filter cake withMeOH and combine 7000.00 g with filtrate. DISTILLATION (30 L ChemGlassJacketed Main Reactor) 11 Distill the reaction at ≤45° C. (100-200 Torrvacuum) to target. Note: Distillation target = 1.5-2.5 mL/g SCC- 5000.00mL 175 charge. PRECIPITATION (30 L ChemGlass Jacketed Main Reactor)ISOLATION (12 L Allen Glass Filter w/30 micron ChemGlass teflon frit) 12Charge water to reactor with moderate agitation 7000.00 g at 40° C. over30-60 min. 13 Agitate the reaction at at 40° C. until crystallizationobserved. 14 Verify crystallization successful. 15 Charge water toreactor with moderate agitation 8000.00 g at 40° C. over 30-60 min. 16Adjust the reaction to 22° C. (20 to 25° C.) over 30-60 min. 17 Filterthe reaction to isolate the product (SCC- 169). 18 Wash the product cakewith MeOH-water (1:9). 8000.00 g 19 Dry the product with agitation andnitrogen bleed for at least 17 h.

Preliminary Single-Solvent Solubility of Compound I:

Solvent Solubility (mg/mL)^(A) EtOH (SDAG-7) 154.8 THF 84.5 iPrOAc 5.1MeOAc 18.2 Water 4.1 ^(A)Solubility was determined by HPLC (responsecurve).

Preliminary Precipitation Studies (MeOH/Water) of Compound I:

Precipitation Studies MeOH/ Addition Precip Concentration SolubilityExperiment Water Mode (Y/N) (mL/g) (mg/mL) 1^(A) 1:3 Normal Y 10 7.02^(A) 1:5 Normal Y 10 5.0 3^(A) 1:9 Normal Y 10 3.6 4^(A)  1:19 Normal Y10 2.7 5^(B) 1:3 Reverse N 80 — +2 parts 1:5 Normal Y 120 ND water^(A)Experiments were conducted on 500 mg scale where the initialsolution in MeOH (via 2447-41) was concentrated to a residue followed bycharging MeOH/water at 25° C. ^(B)Experiment was conducted on 40 mgscale where the initial solution in MeOH (via 2447-41) was chargeddirectly to water. An additional charge of water was required to enableprecipitation.

In Process Precipitation Results (MeOH/Water) of Compound I:

Precipitation Results Concentration Solubility Experiment MeOH/Water(mL/g) (mg/mL) Total Losses 2447-41^(A) 1:9 13 2.5 5.7% 2447-47^(A) 1:510 4.2 6.2%

Example 2. Boc-D-Arg-DMT-OH

Manufacturing Process to Produce Compound 8

Step Operation 1 Charge DMT-OBn HCl (1 eq) and Boc-D-Arg-OH HCl (1.05eq) to the reactor. 2 Charge HOBt (0.1 eq) and DCM (8.5 L/kg of DMT-OBnHCl) to the reactor. 3 Adjust temperature to about 22 ± 3° C. and chargeNMM (2.0 eq) to the reactor 4 Adjust temperature to about 15 ± 3° C. andcharge EDCI (1.05 eq) to the reactor. 5 Adjust temperature to about 15°C. and agitate. 5 Charge EtOH (1.5 L/kg of DMT-OBn HCl) to the reactor 7Agitate for a minimum of 5 hours at 15 ± 3° C. 8 Sample for in-processcontrol reaction completion test, if reaction is not complete, chargeadditional EDCI, stir for a minimum of 1 hour andrepeat the in-processcontrol test until criterion for completion is met. 9 Charge 15% EtOH inDCM. 10 Charge 1M HCl. 11 Adjust temperature to ambient and agitate. 12Stop agitation and separate layers 13 Wash organic layer successivelywith brine, 1M HCl, brine and then brine again 14 Reduce volume viavacuum distillation 15 Adjust temperature to ambient 16 Charge EtOH andreduce volume via vacuum distillation 17 Sample for in-process controlDCM content test, Repeat EtOH addition and volume reduction by vacuumdistillation until the in-process control limit for DCM is met 18 Adjusttemperature to ambient 19 Sample the product for in-process control testfor SCC-192 purity and content

Manufacturing Process to Produce the HCl Salt of Compound II

Step Operation 1 Charge the ethanol solution of Boc-D-Arg-DMT-OBn HCl(SCC-192) 2 Charge 10% Pd/C, 50% wet (w/w) (20 wt. %) 3 Charge EtOH (7L/kg of SCC-192) 4 Agitate and begin hydrogenation around ambienttemperature 5 Step 2B In-Process Control 1: Test for reaction completion5 Filter suspension through filter aid and wash filter cake three timeswith EtOH 7 Reduce volume via vacuum distillation 8 Adjust temperatureto ambient 9 Charge THF and reduce volume via vacuum distillation 10Adjust temperature to ambient 11 Charge THF and reduce volume via vacuumdistillation 12 Adjust temperature to ambient 13 Charge THF and reducevolume via vacuum distillation 14 Step 2B In-Process Control 2: Test forEtOH content 15 Charge iPrOAc and agitate at ambient temperature 16Filter and wash solids three times with iPrOAc 17 Dry the product undervacuum and nitrogen 18 Sample the product for in-process control testfor purity 19 Step 2B In-Process Control 3: Test for Purity

Preparation of the Zwitterionic Form of Compound II

-   -   1. The crude HCl salt is suspended in CH₃OH/H₂O (1/1, v/v)    -   2. The suspension is heated to 45-50° C.    -   3. After the clear solution is formed, an aqueous solution of        Na₂CO₃ (1.2 eq.) is added. During the addition, the solid begins        to precipitate.    -   4. The suspension is stirred for 1 h at 45° C., and then cooled        to 15° C. and stirred for an additional hour.    -   5. The solid is isolated by filtration and dried to provide        Compound II with high purity (99.4 area %) by HPLC. The        calculated w/w assay correcting for residual solvents, water        content and residue on ignition for this demonstration run was        98.7%.

Formation of zwitterionic compound led to high purity material that wasstable, easily handled, and highly crystalline.

Example 3. Crystalline L-Lys(Boc)-Phe-NH₂-XRPD Peak List (Table I)

Angle d Value Net Intensity Gross Intensity Rel. Intensity 4.70418.77211 9559 11528 100.0% 5.230 16.88407 624 2301 6.5% 5.648 15.63394862 2340 9.0% 6.200 14.24402 7663 8912 80.2% 6.650 13.28067 394 14564.1% 7.056 12.51772 508 1400 5.3% 7.709 11.45860 1161 1869 12.1% 8.55310.33046 2135 2771 22.3% 9.402 9.39869 2473 3073 25.9% 9.922 8.907292627 3206 27.5% 10.303 8.57920 1435 1997 15.0% 11.292 7.82975 3301 384834.5% 11.755 7.52244 1985 2530 20.8% 12.265 7.24594 2827 3370 29.6%12.452 7.10258 4581 5123 47.9% 12.655 6.98916 2764 3305 28.9% 13.2706.66655 4117 4655 43.1% 13.778 6.42221 795 1330 8.3% 14.133 6.26164 333866 3.5% 14.462 6.11961 882 1413 9.2% 14.957 5.91833 3726 4255 39.0%15.756 5.61997 7404 7928 77.5% 16.263 5.44580 2360 2881 24.7% 16.5045.36683 5366 5885 56.1% 16.961 5.22337 2930 3447 30.7% 17.107 5.179172585 3100 27.0% 17.658 5.01859 3807 4320 39.8% 17.956 4.93596 4360 487145.6% 18.210 4.86777 4451 4960 46.6% 18.832 4.70852 8963 9468 93.8%19.561 4.53460 3331 3830 34.8% 19.802 4.47996 7877 8375 82.4% 20.2654.37865 1989 2483 2.8% 20.715 4.28449 1746 2237 18.3% 21.514 4.127151756 2241 18.4% 21.958 4.04471 4087 4568 42.7% 22.807 3.89590 3856 433140.3% 23.398 3.79891 779 1248 8.1% 23.660 3.75740 835 1303 8.7% 24.3063.65896 726 1188 7.6% 25.050 3.55198 2158 2614 22.6% 25.462 3.49548 7641217 8.0% 25.709 3.46234 1227 1677 12.8% 26.016 3.42222 714 1161 7.5%26.319 3.38357 521 966 5.5% 26.713 3.33445 662 1103 6.9% 27.411 3.25119709 1143 7.4% 28.356 3.14493 831 1256 8.7% 28.808 3.09564 340 761 3.6%30.662 2.91341 740 1142 7.7% 61.492 2.83854 649 1041 6.8% 35.876 2.50109376 740 3.9% 36.369 2.46832 362 723 3.8%

Example 4. Crystalline Boc-D-Arg-DMT-XRPD Peak List (Table 2)

Angle d Value Net Intensity Gross Intensity Rel. Intensity 8.25310.70448 3779 4204 15.0% 9.353 9.44784 20863 21225 82.9% 12.104 7.3059220016 20338 79.6% 12.809 6.90584 2797 3120 11.1% 13.755 6.43269 1143211758 45.4% 15.709 5.53659 906 1235 3.6% 16.307 5.43127 7500 7829 29.8%16.556 5.35006 12773 13103 50.8% 16.725 5.29645 2495 2825 9.9% 17.5575.04740 22493 22824 89.4% 18.006 4.92236 25154 25485 100.0% 18.7564.72740 18203 18534 72.4% 18.908 4.68953 4809 5141 19.1% 19.414 4.5684812725 13056 50.6% 20.715 4.28417 899 1231 3.6% 21.259 4.17597 5674 540620.2% 22.357 3.97329 3830 4161 15.2% 23.009 3.86218 7511 7842 29.9%23.153 3.83695 2203 2533 8.8% 23.511 3.78085 4659 4989 18.5% 24.2083.57354 7257 7585 28.8% 24.809 3.58598 1940 2268 7.7% 25.060 3.550545627 5954 22.4% 25.767 3.45478 970 1297 3.9% 26.009 3.42308 1418 17445.6% 26.457 3.36613 255 580 1.0% 26.721 3.33347 161 485 0.6% 27.7633.21973 1852 2185 7.4% 28.111 3.17181 1182 1503 4.7% 28.263 3.15505 366687 1.5% 29.111 3.06507 2546 2864 10.1% 29.311 3.04456 1100 1418 4.4%29.652 3.00931 616 933 2.4% 29.912 2.98475 1550 1865 6.2% 30.212 2.955831607 1922 6.4% 30.865 2.89475 1913 2226 7.6% 31.414 2.84540 1565 18766.2% 31.695 2.82084 468 778 1.9% 32.665 2.73926 657 963 2.6% 32.9152.71901 296 602 1.2% 33.805 2.64939 326 632 1.3% 34.165 2.62230 670 9762.7% 34.977 2.56330 485 795 1.9% 36.166 2.48167 798 1113 3.2% 36.5142.45883 611 927 2.4% 36.813 2.43955 364 682 1.4% 37.466 2.39651 173 5020.7% 37.966 2.36808 901 1257 3.6% 38.221 2.35285 394 764 1.6% 38.5762.33202 878 1265 3.5% 39.114 2.30117 394 810 1.6% 39.516 2.27866 363 8011.4%

INCORPORATION BY REFERENCE

All U.S. patents and U.S. and PCT published patent applicationsmentioned in the description above are incorporated by reference hereinin their entirety.

EQUIVALENTS

Having now fully described the present invention in some detail by wayof illustration and examples for the purposes of clarity ofunderstanding, it will be obvious to one of ordinary skill in the artthat the same can be performed by modifying or changing the inventionwithin a range of conditions, formulations and other parameters withoutaffecting the scope of the invention or any specific embodiment thereof,and that such modifications or changes are intended to be encompassedwithin the scope of the appended claims.

We claim:
 1. A crystalline form of Compound (II),

wherein said crystalline form has characteristic peaks in its XRPDpattern at values of two theta as described in Table 2; TABLE 2 NetGross Rel. Angle d value Intensity Intensity intensity 8.253 10.704883779 4204 15.0% 9.353 9.44784 20863 21225 82.9% 12.104 7.30592 2001620338 79.6% 12.809 6.90584 2797 3120 11.1% 13.755 6.43269 11432 1175845.4% 15.709 5.63659 906 1235 3.6% 16.307 5.43127 7500 7829 29.8% 16.5565.35006 12773 13103 50.8% 16.725 5.29645 2495 2825 9.9% 17.557 5.0474022493 22824 89.4% 18.006 4.92236 25154 25485 100.0% 18.756 4.72740 1820318534 72.4% 18.90s 4.68953 4809 5141 19.1% 19.414 4.56848 12725 1305650.6% 20.716 4.28417 899 1231 3.6% 21.259 4.17597 5074 5406 20.2% 22.3573.97329 383u 4161 15.2% 23.009 3.86218 7511 7842 29.9% 23.163 3.836952203 2533 8.8% 23.511 3.78085 4659 4989 18.5% 24.208 3.67354 7257 758528.8% 24.809 3.58598 1940 2268 7.7% 25.060 3.55054 5627 5954 22.4%25.767 3.45478 970 1297 3.9% 26.009 3.42308 1418 1744 5.6% 26.4573.36613 255 580 1.0% 26.721 3.33347 161 485 0.6% 27.763 3.21073 18622185 7.4% 28.111 3.17181 1182 1503 4.7% 28.263 3.15505 366 687 1.5%29.311 3.04456 1100 1418 4.40% 29.662 3.00931 616 933 2.40% 29.9122.98476 1550 1866 6.20% 30.212 2.95583 1607 1922 6.40% 30.865 2.894751913 2226 7.60% 31.414 2.8454 1565 1876 6.20% 31.695 2.82084 468 7781.90% 32.665 2.73926 657 963 2.60% 32.915 2.71901 296 602 1.20% 33.8052.64939 326 632 1.30% 34.165 2.6223 670 976 2.70% 34.977 2.5633 485 7951.90% 36.166 2.48167 798 1113 3.20% 36.514 2.45883 611 927 2.40% 36.8132.43955 364 682 1.40% 37.466 2.39851 173 502 0.70% 37.966 2.36808 9011257 3.60% 38.221 2.35285 394 764 1.60% 38.576 2.33202 878 1266 3.50%39.114 2.30117 394 810 1.60% 39.516 2.27866 363 801 1.40% 29.311 3.044561100 1418 4.40% 29.662 3.00931 616 933 2.40% 29.912 2.98476 1550 18666.20% 30.212 2.95583 1607 1922 6.40% 30.865 2.89475 1913 2226 7.60%31.414 2.8454 1565 1876 6.20% 31.695 2.82084 468 778 1.90% 32.6652.73926 657 963 2.60% 32.915 2.71901 296 602 1.20% 33.805 2.64939 326632 1.30% 34.165 2.6223 670 976 2.70% 34.977 2.5633 485 795 1.90% 36.1662.48167 798 1113 3.20% 36.514 2.45883 611 927 2.40% 36.813 2.43955 364682 1.40% 37.466 2.39851 173 502 0.70% 37.966 2.36808 901 1257 3.60%38.221 2.35285 394 764 1.60% 38.576 2.33202 878 1266 3.50% 39.1142.30117 394 810 1.60% 39.516 2.27866 363 801 1.40%.


2. A crystalline form of Compound (II),

wherein said crystalline form has characteristic peaks in its XRPDpattern as shown in FIG.
 2. 3. A crystalline form of Compound (II),

wherein said crystalline form has characteristic peaks in its XRPDpattern at values of two theta theta (θ 2θ) of: 9.3, 12.1, 16.6, 17.6,18.0, 18.8, and 19.4.
 4. The crystalline form of claim 3, wherein saidcrystalline form has characteristic peaks in its XRPD pattern at valuesof two theta (°2θ) of: 9.3, 12.1, 13.7, 16.3, 16.6, 17.6, 18.0, 18.8,19.4, 21.3, 23.0, 24.2, and 25.1.